P1545: INCIDENCE AND OUTCOMES IN PATIENTS WITH INVASIVE CEREBRAL ASPERGILLOSIS RECEIVING IBRUTINIB TREATMENT: A RETROSPECTIVE ANALYSIS ACROSS FIVE HOSPITALS IN EAST ANGLIA AND SOUTH YORKSHIRE, ENGLAND
Authors: Victor Ling, Sally Keat, Sheraz Bashir, Aritri Mandal, Alexander Keeley, Thomas Locke, Nimish Shah, Joseph Padayatty, Mamatha Karanth, Steve Bougatsias, Sally Taylor, Andy Dann, Deborah Abrams, Nicola Gill, Andrew Hodson, Mahesh Prahladan
Journal: HemaSphere (2023)

Topic: 30. Infections in hematology (incl. supportive care/therapy) Background: Ibrutinib is a small molecule inhibitor that targets Bruton’s tyrosine kinase (BTK), a crucial enzyme in the B cell receptor (BCR) pathway that is responsible for the growth and differentiation of B cells by activating multiple transcription factors and it has become a promising treatment option for various B cell cancers, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and Waldenström’s macroglobulinemia. However, the use of BTK inhibitors has also been linked to an increased risk of invasive fungal infections, as blocking the BTK pathway also inhibits the downstream Nuclear factor of activated T-cells (NFAT) pathway, which impairs neutrophil recruitment. Aims: The aim of this study is to determine the incidence and outcome of invasive cerebral aspergillosis in patients who receive Ibrutinib treatment. Methods: We conducted a retrospective analysis of electronic medical records from four hospitals in East Anglia and a hospital at South Yorkshire to investigate the incidence of invasive cerebral aspergillosis in patients who received Ibrutinib treatment from 2015 onwards. Our study presents a qualitative description of the clinical features, treatments, and outcomes of such patients. Among the 405 patients treated with Ibrutinib for haematological disorders during this period, we identified seven patients who developed cerebral aspergillosis. Among them, six cases were confirmed through biopsy and culture, and one patient was diagnosed presumptively based on imaging. All patients were diagnosed between May 2020 and November 2022 and were between 60 and 81 years old. Results: We identified 7 cases of invasive aspergillosis among the 405 patients across two regions in England. All 7 patients had hematological malignancies and were receiving Ibrutinib for the treatment of their underlying disease. None of the seven patients received prophylactic antifungal therapy at the time of their diagnosis. The mean age of affected patients was 69.29 years, with a range of 61-81. The median time from initiation of Ibrutinib to diagnosis of invasive aspergillosis was 5 months. One of the seven patients died due to invasive aspergillosis or related complications. Four of the patients developed invasive aspergillosis within five months of starting Ibrutinib, while two patient developed the infection after 12 months, and the one patient developed the said infection four years after initiating Ibrutinib treatment. All 7 of them presented with typical increased ICP symptoms like headache, visual disturbances, confusion, and four of them with ataxia. Tests were conducted on all patients to confirm the diagnosis, and imaging showed ring-enhancing lesions in their brains. Six patients underwent further tests to confirm the diagnosis, and one was also found to have pulmonary aspergillosis. Six of the patients underwent neurosurgery and a minimum of six months of antifungal treatment with either Voriconazole or Isavuconazole, and all six of them had complete recovery with complete radiological remission with no residual neurological deficits. One patient unfortunately had significant comorbidity for surgery and died a month later and another patient died from CLL disease progression six months later. Summary/Conclusion: These cases highlight the risk of developing invasive intracerebral aspergillosis with the use of BTK inhibitors, future research could explore the potential benefit of prophylactic antifungal therapy in high-risk patients, identify risk factors for developing invasive aspergillosis with BTK inhibitors, and evaluate the efficacy of different antifungal treatments. Keywords: Invasive aspergillosis, ibrutinib, Fungal infection, Bruton’s tyrosine kinase inhibitor (BTKi)